Non-melanoma skin cancer (NMSC) is the leading cancer diagnosis in the US. Although the mortality rate associated with NMSC is low, the very large and ever-increasing incidence translates into considerable morbidity and an appreciable number of deaths. In addition, considerable resources are necessary to treat over 1 million lesions each year. We have extended a large population based case-control study of nonmelanoma skin cancer in New Hampshire to include genetic susceptibility, and have identified several candidate genes that significantly interact with etiologic exposures to increase risk of NMSC. During the proposed study period we will expand this research to include a total of 1,375 BCC cases, 1,300 SCC cases and 1,500 controls. Importantly, we will also add two high-risk subgroups: early-onset and multiple BCC cases. Three areas of genetic susceptibility will be investigated: modification of UV exposure (MC1R and the glutatathione S-transfemses), DNA damage responsiveness (p53 and p21), and DNA repair proficiency (BER and NER genes). We will test for main gene effects between these polymorphisms and NMSC, as well as gene-environment interactions (i.e. sunburn history, ionizing radiation, and tanning bed use). Finally, given the central role of p53 in photocarcinogenesis, we will assess p53 status in case tumors using immunohistochemistry. We will investigate whether incorporating this biomarker of p53 alteration significantly improves disease classification and estimates of gene-environment interaction in NMSC.